Improvements in therapy for children with cancer have increased the probability of five year survival from less than 30% in 1960 to over 65% in 1986. Because of the young age of these cases, and thus the potential longevity, the delayed consequences of therapy may have a greater impact on their lives, and society at large, than the acute complications of the cytotoxic therapies they have already experienced. The childhood cancer Survivor Study (CCSS) will investigate the long-term effects of cancer and its associated therapies. A retrospective cohort study will be conducted, through a multi-institutional collaboration, which will involve the identification and active follow up of a cohort of approximately 25,000 survivors of cancer, diagnosed under 21 years of age, between 1970 and 1986. The proposed five year project will study children and young adults exposed to specific therapeutic modalities, including radiation, chemotherapy, and/or surgery, for an increased risk of late- occurring events associated with excess mortality and morbidity. For comparison purposes, a variety of data sources will be utilized including: siblings, within cohort, and vital/health statistics. To varying degrees, it has been shown that long-term survivors are at risk of developing second neoplasms, organ dysfunction (e.g. cardiac, gonadal), early death, decreased fertility, offspring with adverse events, and having a family history of cancer. The primary specific aims of the CCSS are not only to expand upon these known late-effects, but to investigate specific hypotheses relating to new risk factors for adverse events and provide information which will facilitate the development of primary and secondary prevention strategies. The cohort will be of sufficient size and heterogeneity with respect to the type of childhood cancer and exposure to radiation, chemotherapeutic agents, and/or surgery to allow for the study of endpoints of interest in this population. Specific risk factors of interest include: (i) original diagnosis; (ii) intensity and duration of exposure to therapeutic radiation and chemotherapeutic agents; (iii) patient characteristics such as sex and age at exposure; and (iv) genetic factors as measured by family history and type of childhood cancer. The size of the study population will allow for assessment of interaction between some of the major risk factors of interest. This project is designed to overcome the limitations (including sample size, selection biases, and lack of heterogeneity of exposures) encountered in single institutional studies of pediatric cancer survivors. The results will provide important information which may be used in the design of future therapeutic strategies and/or interventions to decrease the occurrence or impact of deleterious effects related to treatment exposures and host factors. In addition, the existence of the cohort will provide a dynamic framework and resource for epidemiologists, molecular biologists, oncologists, behavioral scientists, and other disciplines to investigate future questions regarding consequences of therapy, genetic associations, disease processes and causation, and quality of life questions.